The c-kit gene is the normal homologue of v-kit, the HZ4 feline sarcoma virus oncogene. It resides on human chromosome 4. The gene encodes a dimeric transmembrane glycoprotein receptor with tyrosine kinase activity that appears to be highly related to the receptors for colony stimulating factor-1 and platelet derived growth factor. (Yarden et. al., The EMBO Journal, 6, 3341-3351 (1987)). Like these receptors, c-kit also appears to belong to the immunoglobulin gene superfamily.
The mouse c-kit gene has been mapped to chromosome 5 where it was determined to be allelic with the dominant white spotting locus (W) (Chabot et al., Nature 335, 88-89 (1988). C-kit mutations are commonly found in W mice and, in addition to abnormalities affecting coat color and gonadal development, they also have a variety of hematopoietic defects. Macrocytic anemia is one of the most striking and profound of these abnormalities. The W.sup.42 mutation, associated with a particularly severe hematologic manifestation, has been shown to be due to a missense mutation leading to replacement of one amino acid and defective tyrosine kinase activity (Tan et al., Science 247, 209 (1990)). Such animals are also known to have about one-third of the erythroid burst forming units of healthy wild-type littermates (Goldwather et al., Exp. Heme. 18, 936 (1990)).
The ligand for the c-kit receptor has now been identified, molecularly cloned and expressed (Yarden et. al., The EMBO Journal, 6, 3341-3351 (1987)). The encoded protein, known as stem cell factor (SCF), mast cell growth factor (MGF), or steel factor (SLF) is the product of a gene which resides at the steel (S1) locus. Mice with S1 mutations have phenotypic abnormalities quite similar to those of W mice. The W mouse lacks, or has defects in, a critical signal transducing receptor encoded by c-kit. The S1 mouse has defects in the ligand which stimulates the receptor.
The importance of the c-kit ligand-receptor system in human hematopoiesis is unclear. No human mutations at the corresponding locii have been described. Studies in mice may have very limited applicability to human systems. Moreover, even if a tissue is shown to express a particular message, the importance of the message to expression of a cellular phenotype is not known until the cell is deprived of the encoded protein. Biological systems are redundant. Lack of a protein can often be compensated by another protein of the same family. It is therefore not predictable that inhibition of expression of a particular gene will result in altered phenotype.